Protons have a physical dose advantage over photons (x-rays), the most commonly used type of radiation therapy for cancer patients, because they do not exit beyond the tumor target and thus irradiate less normal tissue. Irradiation of normal tissue yields no possible benefit for the patient; it can only increase the risk of treatment related side effects during and long after the end of treatment. While proton radiation therapy has been used in selective clinical sites with significant improvements in clinical outcome, we believe that research into better control of the finite range of the proton in the patient can yield additional clinical gains. The major objective of this project, Improving the Therapeutic Ratio of Proton Radiation Therapy in Challenging Clinical Sites, is to perform clinical trials employing improved control of the proton range in challenging clinical scenarios. We believe that these research advances should translate into further improvement in outcome in not only these particular diseases, but at multiple other anatomic sites where proton radiation therapy is increasingly being employed. The potential impact for public health is higher cancer cure rates and/or reduced treatment side effects, particularly in children, who are at the highest risk of late radiation therapy-induced side effects, which can be reduced with the use of protons. The specific aims are to conduct phase II clinical studies in patients with unresectable liver tumors, pediatric medulloblastoma and rhabdomyosarcoma, spine and skull base sarcomas, and paranasal sinus tumors in which we will (1) use the end of range of the proton more effectively, (2) investigate the clinical use of magnetically scanned proton beams and intensity-modulated proton therapy, (3) confirm the tolerability and effectiveness of hypofractionated radiation dose escalation for unresectable liver tumors, (4) critically assess the importance of an adaptive proton radiation therapy strategy in response to tumor and normal tissue responses to radiation therapy in one anatomic site, and (5) compare treatment-related morbidity with photons and protons in these selected pediatric malignancies and in adult paranasal sinus tumors. The physical tools necessary to achieve these clinical goals will be investigated in Projects 3 and 4. The initial use of many of these physical tools in Project 2 will be important for their later use in Project 1, Proton Dose Escalation and Proton vs. Photon Randomized Trials for Non-Small Cell Lung Cancer.